bluuebunny/crossref_metadata_2025 huggingface dataset:
People with Impaired Glucose Tolerance and Impaired Fasting Glucose Are Similarly Susceptible to Cardiovascular Disease: A Study in First-Degree Relatives of Type 2 Diabetic Patients
Authors: Amini Massoud , Horri Negar , Zare Maryam , Haghighi Sassan , Hosseini Seyed Mohsen , Aminorroaya Ashraf , Hovsepian Silva
Published: April 2010

Background/Aims: To compare the cardiovascular disease (CVD) risk factors between subjects with impaired fasting glucose (IFG) and those with impaired glucose tolerance (IGT) in the first-degree relatives (FDR) of type 2 diabetic patients. Methods: A cross-sectional study, conducted between 2004 and 2006 in 1,893 (1,412 females and 481 males) FDR of type 2 diabetic outpatients of the Isfahan Endocrine and Metabolism Research Center. In all participants, blood pressure, weight, height, waist circumference, serum lipids and HbA1c were measured and a standard 75-g 2-hour oral glucose tolerance test was performed. The diagnosis of IGT, IFG and diabetes was made according to American Diabetes Association criteria. Results: Isolated IGT and isolated IFG, and both IFG and IGT were observed in 8.8%, 17.4% and 11.2% of subjects, respectively. In comparison to subjects with normal glucose levels and tolerance (control group): the mean waist circumference was significantly higher in both IFG and IGT groups; BMI, HDL-c and LDL-c in the IFG group; and triglycerides in the IGT group. The means of all studied CVD risk factors were significantly higher in the IGT+IFG group than the control group, except for blood pressure, HDL-c and HbA1c. No significant differences were found regarding CVD risk factors between IFG and IGT groups. Conclusions: The prevalence of IFG and IGT is high in FDR of type 2 diabetic patients. CVD risk factors are similar in these 2 groups and higher than in the control group. More attention should be paid to screening and treatment of this high-risk population.
Perinatal Outcome of Conservative Management versus Fetal Intervention for Twin Reversed Arterial Perfusion Sequence with a Small Acardiac Twin
Authors: Jelin Eric , Hirose Shinjiro , Rand Larry , Curran Patrick , Feldstein Vickie , Guevara-Gallardo Salvador , Jelin Angie , Gonzales Kelly , Goldstein Ruth , Lee Hanmin
Published: April 2010

Objective: To examine the outcomes of patients with twin reversed arterial perfusion (TRAP) sequence in which the acardiac twin was ≤50% the weight of the pump twin. Methods: This was a retrospective study conducted with institutional review board approval. The records of all patients referred to UCSF for suspected diagnosis of TRAP between 1994 and 2009 were reviewed (n = 76). Patients with pregnancies complicated by TRAP with an acardiac twin ≤50% the weight of the pump twin were included (21 patients). Exclusion criteria were loss to follow-up (1 patient) and syndromic abnormalities in the pump twin (2 patients). Results: Of the 18 patients with viable pregnancies that met the criteria for analysis, 7 (39%) underwent radiofrequency ablation (RFA) of the acardiac twin and 11 (61%) underwent conservative management. None of the pump twins in either group had hydrops fetalis. Three of the 11 acardiac twins in the conservative management group did not undergo RFA because they did not have blood flow at presentation to UCSF. Survival to delivery was 100% (7/7) in the RFA group and 91% (10/11) in the conservative management group. When we eliminated from our analysis the 3 pregnancies in the conservative management group without blood flow to the acardiac twin, survival to delivery was 88% (7/8). The single death occurred in 1 of the 3 monochorionic-monoamniotic pregnancies in the conservative management group, all of whom had blood flow to the acardiac twin. There were no statistically significant differences in gestational age at delivery, birth weight or survival between the RFA and conservative management groups, even after stratification by blood flow. Conclusions: Conservative management with close monitoring appears to be a safe option for TRAP pregnancies in which the acardiac twin is ≤50% the weight of the pump twin.
Islamic Fasting and Health
Authors: Azizi Fereidoun
Published: April 2010

Background: Muslims fast from sunrise to sunset during the month of Ramadan, the 9th lunar month. The duration of fasting varies from 13 to 18 h/day. Fasting includes avoidance of drinking liquids and eating foods. The aim of this article is to review health-related aspects of Ramadan fasting. Methods: Related abstracts from 1960 to 2009 were obtained from Medline and local journals in Islamic countries. One hundred and thirteen articles meeting the criteria for paper selection were reviewed in depth to identify details of related materials. Results: During the fasting days of Ramadan glucose homeostasis is maintained by meals taken before dawn and by liver glycogen stores. Changes in serum lipids are variable and depend on the quality and quantity of food consumption and changes in weight. Compliant, well-controlled type 2 diabetics may observe Ramadan fasting, but fasting is not recommended for type 1, noncompliant, poorly controlled and pregnant diabetics. There are no adverse effects of Ramadan fasting on the heart, lung, liver, kidney, eyes, hematologic profile, endocrine and neuropsychiatric functions. Conclusions: Although Ramadan fasting is safe for all healthy individuals, those with various diseases should consult their physicians and follow scientific recommendations.
Korean Version of Frontal Assessment Battery: Psychometric Properties and Normative Data
Authors: Kim Tae Hui , Huh Yoonseok , Choe Jin Yeong , Jeong Ji Woon , Park Joon Hyuk , Lee Seok Bum , Lee Jung Jae , Jhoo Jin Hyeong , Lee Dong Young , Woo Jong Inn , Kim Ki Woong
Published: April 2010

Background: We developed the Korean version of the Frontal Assessment Battery (FAB-K), evaluated its psychometric properties and constructed normative data for Korean elders. Methods: FAB-K was administered to 300 Alzheimer’s disease (AD) patients and 635 normal controls. Reliability of FAB-K was evaluated by testing its internal consistency, test-retest and inter-rater reliabilities. Validity of FAB-K was evaluated by testing discriminant validity for AD and concurrent validity with other frontal function tests. Age- and education-specific normative data of FAB-K were developed. Results: Cronbach’s α, inter-rater reliability and test-retest reliability of FAB-K were 0.802, 0.980 (p < 0.001) and 0.820 (p < 0.001), respectively. FAB-K exhibited significant correlations with the scores of MMSE and other frontal function tests (p < 0.01). Total and item scores of FAB-K were lower in AD patients than in controls and became worse as clinical dementia rating increased (F = 192.026, d.f. = 4, p < 0.001). The optimal cut-off score of FAB-K for AD was determined as 10/11, where sensitivity and specificity for AD were 0.717 and 0.827, respectively. Normative data were stratified by 3 age groups and 4 education groups. Conclusion: The FAB-K is a valid and reliable instrument for evaluating frontal dysfunction, and may be useful for screening AD.
Testing Haplotype-Environment Interactions Using Case-Parent Triads
Authors: Shi Min , Umbach David M. , Weinberg Clarice R.
Published: April 2010

Objective: Joint analysis of multiple SNP markers can be informative, but studying joint effects of haplotypes and environmental exposures is challenging. Population structure can involve both genes and exposures and a case-control study is susceptible to bias from either source of stratification. We propose a procedure that uses case-parent triad data and, though not fully robust, resists bias from population structure. Methods: Our procedure assumes that haplotypes under study have no influence on propensity to exposure. Then, under a no-interaction null hypothesis (multiplicative scale), transmission of a causative haplotype from parents to affected offspring might show distortion from Mendelian proportions but should be independent of exposure. We used this insight to develop a permutation test of no haplotype-by-exposure interaction. Results: Simulations showed that our proposed test respects the nominal Type I error rate and provides good power under a variety of scenarios. We illustrate by examining whether SNP variants in GSTP1 modify the association between maternal smoking and oral clefting. Conclusion: Our procedure offers desirable features: no need for haplotype estimation, validity under unspecified genetic main effects, tolerance to Hardy-Weinberg disequilibrium, ability to handle missing genotypes and a relatively large number of SNPs. Simulations suggest resistance to bias due to exposure-related population stratification.
Phonetic Duration, Phonological Quantity and Prosodic Structure in Inari Saami
Authors: Bye Patrik , Sagulin Elin , Toivonen Ida
Published: April 2010

Inari Saami, an endangered Finno-Ugric language of Northern Finland, is reported to have a three-way surface contrast in consonant length (short, halflong and long). We studied disyllabic words (C)V1CxV2(C) using data from 5 native speakers under two conditions, with short and long preceding vowel, V1, and found support for the claim that Inari Saami has a ternary contrast in consonant length. The three-way length contrast is more robust following a short V1. The duration of V2 correlates negatively with the length of the medial consonant. However, there is one major departure from this pattern. When both V1 and the medial consonant are long, V2 is also longer. This finding supports the idea that disyllables of this class differ from the others in their prosodic structure in having two metrical feet rather than one. This interpretation tallies with independent evidence from synchronic morphophonology and the historical development of the prosodic system of Inari Saami.
Vowel Discrimination by English, French and Turkish Speakers: Evidence for an Exemplar-Based Approach to Speech Perception
Authors: Ettlinger Marc , Johnson Keith
Published: April 2010

Recent studies of speech perception have shown that speakers retain significant amounts of the phonetic detail of heard speech providing strong evidence for an exemplar-based model of the representation of speech sounds. This does not preclude the existence of a feature-based model as well; indeed many theories of speech perception advocate a feature- or contrast-based model for the discrimination of speech sounds. In this study, we provide evidence that an exemplar-based model of speech perception makes more accurate predictions for the performance of English, French and Turkish speakers in a vowel discrimination task. Participants were asked to discriminate the four high front vowels of German, which differ by both the rounding and tense/lax contrasts. Crucially, English has only the tense/lax contrast, while Turkish and French have only rounding. The results show that having one of the vowels in one’s language facilitates discrimination more than having the featural contrast supporting an exemplar-based model. Furthermore, different discrimination tasks were used showing that the effects of native language on vowel discrimination are mediated by task and by psychoacoustic similarity.
Cross-Reactivity in Drug Hypersensitivity Reactions to Sulfasalazine and Sulfamethoxazole
Authors: Zawodniak Anna , Lochmatter Priska , Beeler Andreas , Pichler Werner J.
Published: April 2010

Background: Sulfonamides are generally classified into 2 groups: antibiotics and non-antibiotics. Recent studies showed that patients allergic to sulfonamide antibiotics do not have a specific risk for an allergy to sulfonamide non-antibiotic. However, the anti-inflammatory drug sulfasalazine represents an important exception. Used in rheumatic diseases, it is classified as a non-antibiotic sulfonamide, but is structurally related to antibiotic sulfonamides. Therefore, we aimed to analyze in vitro the cross-reactivity between the antimicrobial sulfamethoxazole and the anti-inflammatory drug sulfasalazine. Methods: PBMC from 2 patients with severe hypersensitivity syndrome to sulfasalazine, 3 patients with sulfamethoxazole allergy and 5 healthy donors were isolated and incubated with medium only (negative control), 2 concentrations (10, 100 µg/ml) of sulfapyridine, 2 concentrations (100, 200 µg/ml) of sulfamethoxazole, and tetanus toxoid (10 µg/ml) as a positive control. After 6 days of culture, 3H-thymidine was added and cell proliferation was measured. Results: In all patients tested, the lymphocyte transformation tests were positive for both sulfapyridine and sulfamethoxazole, suggesting a strong cross-reactivity to these drugs. None of the healthy donors reacted to any of the drugs tested. We refrained from provoking our patients with either sulfasalazine or sulfamethoxazole, as they had a clear, typical history, severe symptoms and were positive on in vitro tests to both compounds. Conclusions: We demonstrate that in the case of sulfamethoxazole and sulfasalazine, cross-reactivity is dependent on chemical features rather than the indication of the drugs. Therefore, patients with hypersensitivity to sulfasalazine or sulfamethoxazole should be specifically advised to avoid both drugs.
CD8 and CD103 Are Highly Expressed in Asthmatic Bronchial Intraepithelial Lymphocytes
Authors: Hirosako Susumu , Goto Eisuke , Tsumori Kaori , Fujii Kazuhiko , Hirata Naomi , Ando Makoto , Kohrogi Hirotsugu
Published: April 2010

Background: Although characteristics of intraepithelial lymphocytes (IELs) in mucosal immunity have been well defined in the intestine, bronchial IELs have been little investigated. Recently, we showed that bronchial IELs have a distinct function that partly resembles that of intestinal IELs; however, surface antigen expression of bronchial IELs and the relationship of that expression to airway disease have not been studied. Methods: We analyzed phenotypic profiles of human bronchial IELs and lamina propria lymphocytes (LPLs) by double-staining immunohistochemistry using full-thickness bronchial specimens (10 nonasthmatic controls and 7 asthmatics) from lung resections. Results: In controls, the percentage of CD4+ cells was lower, and the percentage of CD8+ cells was higher in IELs compared to LPLs (CD4: median 50.0% in IELs vs. 65.9% in LPLs, p = 0.01; CD8: 50.9% in IELs vs. 34.4% in LPLs, p = 0.007). The percentage of cells positive for CD103 (αE-integrin) was higher in IELs than that in LPLs (median 60.1% in IELs vs. 16.9% in LPLs; p < 0.001). In IELs from asthmatics, these characteristics were particularly significant (CD4: median 26.2%, p = 0.008; CD8: 79.8%, p = 0.007; CD103: 76.2%, p = 0.019; all compared with IELs from nonasthmatics). Conclusions: These results suggest that human bronchial IELs have roles distinct from subsets of other lymphocytes, and that CD8+ cells and CD103+ cells have potentially important functions in the bronchial epithelium.
Genetic Polymorphisms of ADRB2 and IL10 May Be Associated with the Risk of IgE Sensitization to Digestive Powders in Exposed Medical Personnel
Authors: Ye Young-Min , Lee Hyun-Young , Kim Sang-Hoon , Kim Sang-Ha , Kim Seung-Hyun , Park Hae-Sim
Published: April 2010

Background: It has been reported that pancreatic extracts may induce IgE-mediated respiratory allergy in medical personnel. The aim of the study was to identify genetic factors associated with IgE sensitization to digestive powders containing pancreatic extract. Methods: This case-control study was performed on 153 subjects routinely exposed to digestive powder and on 123 nonexposed controls working in Ajou University Hospital. Skin prick testing was performed using 4 commonly used digestive powders and α-amylase. Serum specific IgE levels were measured by ELISA. Three single nucleotide polymorphisms, ADRB2 46A>G, IL10 –1082A>G and IL4 –589T>C, were genotyped using the single base extension method. Results: The positive rate of serum specific IgE to digestive powder was significantly higher in the 41 (26.8%) exposed personnel with work-related respiratory symptoms than in controls (24.4 vs. 5.4%, p = 0.012). Thirty-nine (25.5%) of the 153 exposed personnel were found to have an allergy to digestive powder, as determined by a positive skin prick test and/or a high serum specific IgE level to digestive powder. The ADRB2 46A>G and IL10 –1082A>G polymorphisms were found to be significantly associated with the development of an allergy to digestive powder in exposed medical personnel by multiple logistic regression analysis after controlling for age, atopy and job type (pharmacist or nurse; p = 0.035 and p = 0.027, respectively). Conclusion: These results suggest that the genetic polymorphisms ADRB2 46A>G and IL10 –1082A>G are genetic factors that increase IgE sensitization to pancreatic extracts in medical personnel occupationally exposed to digestive powders.
Warfarin Therapy That Results in an International Normalization Ratio above the Therapeutic Range Is Associated with Accelerated Progression of Chronic Kidney Disease
Authors: Brodsky Sergey V. , Collins Michael , Park Edward , Rovin Brad H. , Satoskar Anjali A. , Nadasdy Gyongyi , Wu Haifeng , Bhatt Udayan , Nadasdy Tibor , Hebert Lee A.
Published: April 2010

Background/Aims: We had previously reported that acute kidney injury (AKI) in warfarin-treated chronic kidney disease (CKD) patients may occur shortly after an acute increase in the International Normalization Ratio (INR) >3.0 with formation of occlusive red blood casts. Recovery from this warfarin-associated AKI is poor. Here we investigated whether excessive warfarin therapy could accelerate the progression of CKD. Methods: We analyzed serum creatinine (SC) and INR in 103 consecutive CKD patients on warfarin therapy in our Nephrology program from 2005 to the present. Results: Forty-nine patients experienced at least 1 episode of INR >3.0. Of these, 18 patients (37%, Group 1) developed an unexplained increase in SC ≧0.3 mg/dl coincident with INR >3.0 (mean SC increase 0.61 ± 0.44 mg/dl); 31 patients (63%, Group 2) showed stable SC (mean SC change 0.04 ± 0.19 mg/dl). Subsequent CKD progression was accelerated in Group 1, but not in Group 2. The 2 groups were not different with respect to demographics, comorbidities, blood pressure, or therapies. However, African Americans were overrepresented in Group 1 (p = 0.035). Conclusions: Overanticoagulation is associated with faster progression of CKD in a high percentage of patients. Our results indicate the need for prospective trials. Nevertheless, we suggest that our findings are sufficiently compelling at this point to justi- fy extra caution in warfarin-treated CKD patients to avoid overanticoagulation.
Intradialytic Hypertension: It Is Time to Act
Authors: Chazot Charles , Jean Guillaume
Published: April 2010

Intradialytic hypertension (IDH) is defined by blood pressure (BP) values during and at the end of the dialysis session exceeding BP values at dialysis onset. It occurs in around 10% of hemodialysis (HD) patients. It is associated with HD patients’ hospitalization and increased risk of death. Many hypotheses have been proposed to explain this phenomenon. Recent studies and reports highlight the important role of fluid overload, hemodynamic changes, and increased endothelin level. The importance of other hypotheses such as the renin-angiotensin system activation, sympathetic overactivity and ionic variations seems secondary but it deserves to be confirmed. Fluid removal remains the key point for treating IDH. Several important unanswered questions remain and the need for further research is highlighted.
Intima-Media Thickness Is Associated with Inflammation and Traditional Cardiovascular Risk Factors in Non-Dialysis-Dependent Patients with Chronic Kidney Disease
Authors: Lemos Marcelo M. , Jancikic Alessandra D.B. , Sanches Fabiana M.R. , Christofalo Dejaldo M. , Ajzen Sérgio A. , Carvalho Aluízio B. , Draibe Sérgio A. , Canziani Maria Eugênia F.
Published: April 2010

Background: Mortality due to cardiovascular causes is high in chronic kidney disease (CKD). Intima-media thickness (IMT) and inflammation are early atherosclerosis markers, although data are lacking about their association in the CKD non-dialysis-dependent (CKD-NDD) population. The aim of the present study was to evaluate the association between IMT, inflammation and other cardiovascular risk factors in such patients. Methods: CKD-NDD patients (n = 122) were subjected to measurements of carotid IMT and inflammatory marker levels in a cross-sectional study. Results: Mean patient age was 55.2 ± 11.3 years (61.5% males). Median C-reactive protein (CRP) was 0.28 mg/dl (0.03–14.2). The median interleukin (IL)-6 count was 4.75 pg/ml (0.7–243), the mean adiponectin was 27.8 ± 7.3 ng/ml and the mean IMT was 0.61 ± 0.19 mm. Four (3.3%) patients had IMT above the normal range. IMT was higher in males (p < 0.001), patients with estimated glomerular filtration rate <60 ml/min (p = 0.030), inflammation (p = 0.005) and higher IL-6 levels (p = 0.023). IMT was correlated with age (R = 0.538; p < 0.001), waist circumference (R = 0.235; p = 0.016), CRP (R = 0.191; p = 0.035) and systolic blood pressure (R = 0.181; p = 0.048). In a multiple regression analysis, the independent determinants of IMT were age (β = 0.512; p < 0.001) and CRP levels (β = 0.159; p = 0.041). Conclusion: The present study demonstrated that although the IMT values were within the normal range, there was a clear association of IMT with age, as well as with inflammation in an asymptomatic CKD-NDD population.
Diagnostic Value of Urinary Dysmorphic Erythrocytes in Clinical Practice
Authors: Crop Meindert J. , de Rijke Yolanda B. , Verhagen Paul C.M.S. , Cransberg Karlien , Zietse Robert
Published: April 2010

Background: In clinical practice, discriminating between glomerular and nonglomerular causes of hematuria is often difficult. Dysmorphic red blood cells (dRBC) in the urinary sediment are claimed to be effective, but the cutoff points in the literature vary. This follow-up study aimed to determine the diagnostic value of dRBC. Methods: We investigated 134 hematuria patients in the departments of nephrology and urology. To diagnose the origin of hematuria, urological and/or nephrological examination was performed and the %dRBC identified by microscopy. Follow-up was performed after 3.5 years. Results: The cause of hematuria was proven in 68 patients (35% glomerular; 65% nonglomerular). Patients with glomerular disease had significantly more albuminuria and dRBC than patients with nonglomerular disease, but the %dRBC ranged from 1 to 50% and no optimal cutoff could be identified. Logistic regression analysis showed that %dRBC had a predicted probability to diagnose glomerular disease of 77.9% (area under the curve, AUC, 0.85). When %dRBC was combined with other risk factors such as serum creatinine, sex, age, dipstick erythrocyte or proteinuria score and number of casts, the predictive probability increased to 90.6% (AUC 0.97). Follow-up of the included patients showed no benefit of dRBC to identify patients at risk for glomerular disease. Conclusions: The diagnostic value of routinely collected urinary dRBC to diagnose glomerular disease in patients presenting with hematuria is modest. However, including dRBC with other variables, such as age and erythrocyte score on dipstick testing may increase the sensitivity, but needs to be confirmed in another, preferably larger, population.
Cardiovascular Effects of Growth Hormone in Adult Hemodialysis Patients: Results from a Randomized Controlled Trial
Authors: Kober Lars , Rustom Rana , Wiedmann Jonas , Kappelgaard Anne-Marie , El Nahas Meguid , Feldt-Rasmussen Bo
Published: April 2010

Background/Aims: The high morbidity and mortality rates in hemodialysis (HD) patients are due, at least in part, to their increased risk for cardiovascular diseases (CVD). This prospective study evaluated the effect of growth hormone (GH) on a number of CVD risk markers in adult patients on HD. Methods: 139 HD patients were randomized to one of three GH doses or to placebo. Change from baseline in lean body mass (LBM), CVD risk markers (e.g. lipid profile, plasma homocysteine, inflammatory markers, blood pressure, IGF-I, IGFBP-3 and echocardiography) and correlations with serum IGF-I levels and body mass index were evaluated. Results: LBM increased in GH-treated groups compared with placebo (p < 0.001 pooled GH groups vs. placebo). IGF-I (p = 0.0027) and serum high-density-lipoprotein cholesterol levels (p = 0.038) increased with GH treatment. Serum low-density-lipoprotein cholesterol showed a trend to reduction. IGF-I was negatively correlated with plasma homocysteine levels (p = 0.01) and systolic blood pressure (p < 0.0001). Logistic regression analysis showed that interleukin-6, ghrelin and hematocrit values were significant determinants of all-cause mortality. Left ventricular mass was unchanged from baseline in GH-treated groups. Conclusion: In adult HD patients, GH treatment had a predominantly beneficial effect on CVD risk markers.
Maternal Thyroid Function at 11–13 Weeks of Gestation
Authors: Ashoor Ghalia , Kametas Nikos A. , Akolekar Ranjit , Guisado Julia , Nicolaides Kypros H.
Published: April 2010

Objective: To establish normal ranges of maternal serum thyroid-stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3) at 11–13 weeks of gestation. Methods: Maternal serum concentrations of FT3, FT4, TSH, anti-thyroperoxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies were measured at 11–13 weeks. Normal ranges were constructed from the data of singleton pregnancies with no anti-thyroid antibodies resulting in live births after 34 weeks of phenotypically normal neonates with birth weight above the 5th percentile. Adjustments were made for maternal characteristics found by multiple regression analysis to affect the levels of TSH, FT3 and FT4. Results: 3,592 of the 4,318 pregnancies examined were antibody negative, and in this group serum TSH increased whereas FT3 and FT4 decreased with gestation, and all three were lower in black than in white women. Serum FT3 and FT4 decreased but TSH did not change significantly with maternal age; TSH and FT3 increased whereas FT4 decreased with body mass index; TSH decreased whereas FT3 and FT4 increased with serum free β-hCG. In the antibody-positive group, compared to the negative group, median TSH was higher and median FT3 and FT4 were lower. Conclusion: The study established normal ranges for maternal thyroid function at 11–13 weeks.
Comparison of Bevacizumab and Triamcinolone for Treatment of Macular Edema Secondary to Branch Retinal Vein Occlusion in a Pair-Matched Analysis
Authors: Guthoff Rainer , Meigen Thomas , Hennemann Kathrin , Schrader Wolfgang
Published: April 2010

Background: To compare the outcome of bevacizumab or triamcinolone acetate (TA) treatment in patients with macular edema (ME) after branch retinal vein occlusion (BRVO). Methods: In a retrospective assessment, 10 bevacizumab-treated patients and 10 TA-treated with ME after BRVO were pair-matched according to initial best-corrected visual acuity (BCVA) and central macular thickness (CMT) as measured by Stratus optical coherence tomography (OCT). BCVA and CMT were the main endpoints. Results: The initial BCVA was 0.2 ± 0.13 in bevacizumab-treated patients and 0.2 ± 0.16 in TA-treated patients, with a CMT of 497 ± 102 µm and 517 ± 88 µm, respectively. Following bevacizumab, the mean final BCVA increased by 2.8 ± 4 lines, and by 0.6 ± 3.5 lines in patients receiving TA. The mean final CMT was 238 ± 118 µm and 195 ± 243 µm in the respective treatment groups. Conclusions: Both treatments decreased the CMT, but only bevacizumab induced an improvement in BCVA from baseline, which was significant 8 weeks after treatment, but no longer significant after 13 months.
NF-ĸB and Bcl-3 Activation Are Prognostic in Metastatic Colorectal Cancer
Authors: Puvvada Soham D. , Funkhouser William K. , Greene Kevin , Deal Allison , Chu Haitao , Baldwin Albert S. , Tepper Joel E. , O’Neil Bert H.
Published: April 2010

Purpose: NF-ĸB is an antiapoptotic transcription factor that has been shown to be a mediator of treatment resistance. Bcl-3 is a regulator of NF-ĸB that may play a role in oncogenesis. The goal of this study was to correlate the activation status of NF-ĸB and Bcl-3 with clinical outcome in a group of patients with metastatic colorectal cancer (CRC). Methods: A retrospective study of 23 patients who underwent surgical resection of CRC at the University of North Carolina (UNC). Activation of NF-ĸB was defined by nuclear expression of select components of NF-ĸB (p50, p52, p65) and Bcl-3. Tissue microarrays were created from cores of normal mucosa, primary tumor, lymph node metastases and liver metastases in triplicate from disparate areas of the blocks, and an intensity score was generated by multiplying intensity (0–3+) by percent of positive tumor cells. Generalized estimating equations were used to note differences in intensity scores among normal mucosa and nonnormal tissues. Cox regression models were fit to see if scores were significantly associated with overall survival. Results: p65 NE was significantly higher in primary tumor and liver metastases than normal mucosa (both p < 0.01). p50 nuclear expression was significantly higher for all tumor sites than for normal mucosa (primary tumor and lymph node metastases p < 0.0001, liver metastases p < 0.01). Bcl-3 nuclear expression did not differ significantly between normal mucosa and tumor; however, nuclear expression in primary tumor for each of these components was strongly associated with survival: the increase in hazard for each 50-point increase in nuclear expression was 91% for Bcl-3, 66% for p65, and 52% for p50 (all p < 0.05). Conclusions: Activation of canonical NF-ĸB subunits p50 and p65 as measured by nuclear expression is strongly associated with survival suggesting NF-ĸB as a prognostic factor in this disease. Primary tumor nuclear expression appears to be as good as, or better than, metastatic sites at predicting prognosis. Bcl-3 nuclear expression is also negatively associated with survival and deserves further study in CRC.
Does Guideline-Adherent Therapy Improve the Outcome for Early-Onset Breast Cancer Patients?
Authors: Varga Dominic , Wischnewsky Manfred , Atassi Ziad , Wolters Regine , Geyer Verena , Strunz Kathrin , Kreienberg Rolf , Woeckel Achim
Published: April 2010

Background and Objective: Guidelines for the treatment of early-onset breast cancer have been proposed in several countries, but to date, their impact on outcomes is unverified. The objective of this study was to evaluate the association between guideline-adherent versus nonadherent treatment and recurrence-free survival (RFS) and overall survival (OAS) in early-onset breast cancer patients. Methods: A total of 1,778 patients were included in the study, of whom 111 were 35 years or younger and 1,667 were between 36 and 55 years. RFS and OAS were compared between the two groups, with respect to multiple parameters. All survival data were adjusted for tumor characteristics and analyzed with respect to guideline adherence according to the German Step 3 guidelines. Results: Statistically significant differences between the two groups (<35 years, 36–55 years) were observed with regard to breast surgery (p = 0.002) and hormone therapy (p = 0.006). Both groups were treated identically in terms of guideline adherence concerning axillary dissection (p = 0.9), radiation therapy (p = 0.7) and chemotherapy (p = 0.556). Young breast cancer patients whose treatment adhered to guideline recommendations had increased RFS and OAS [RFS: p = 0.030, hazard ratio (HR) 2.95, 95% confidence interval (CI) 1.11–7.83; OAS: p ≤ 0.001, HR 2.92, 95% CI 2.01–4.23]. Conclusion: Guideline-adherent treatment for early-onset breast cancer patients significantly improves OAS and RFS and should therefore be demanded for all patients.
Effect of Human Colorectal Carcinogenesis on the Neural Cell Adhesion Molecule Expression and Polysialylation
Authors: Fernández-Briera A. , García-Parceiro I. , Cuevas E. , Gil-Martín E.
Published: April 2010

Objective: Although downregulation of neural cell adhesion molecule (NCAM) has been correlated with poor prognosis in colorectal cancer (CRC), it is also possible that colon cancer spreading comes from reducing tumor cell adhesion through NCAM polysialylation, as occurs in lung carcinoma or Wilms’ tumor. Methods: To prove this hypothesis, we have performed a prospective study on tumor and control specimens from 39 CRC patients, which were immunostained for NCAM and PSA (polysialic acid) expression. Results: Tumor versus control expression of NCAM and PSA epitopes in tissue specimens, as well as correlation between tumor expression and clinicopathological features, were statistically analyzed. Results showed a low constitutive expression of NCAM and PSA (PSA-NCAM) in control tissue, which reached a statistically significant increase in the tumor tissue. Likewise, the presence and number of lymph node metastases at surgery were correlated with NCAM expression and PSA/NCAM coexpression. Conclusions: These data highlight the importance of taking into account PSA-associated epitopes when dealing with NCAM cell expression studies in tumor development and progression. The analysis of PSA and NCAM expression in CRC suggests a new way, other than downregulation of NCAM, in order to escape contact inhibition and promote cell tumor spreading in colorectal cancer.
Dietary Methionine Restriction with FOLFOX Regimen as First Line Therapy of Metastatic Colorectal Cancer: A Feasibility Study
Authors: Durando Xavier , Farges Marie-Chantal , Buc Emmanuel , Abrial Catherine , Petorin-Lesens Caroline , Gillet Brigitte , Vasson Marie-Paule , Pezet Denis , Chollet Philippe , Thivat Emilie
Published: April 2010

The methionine (MET) dependency of tumor cells opens interesting perspectives for targeting tumor cells and potentiating chemotherapy treatment, like 5-fluorouracil (5-FU) and platinum compound. Since MET deprivation can individually potentiate the different chemotherapeutic agents used in the 48-hour combined regimen of 5-FU, leucovorin and oxaliplatin (FOLFOX) regimen, we initiated a feasibility study associating dietary MET restriction with the FOLFOX regimen in patients with metastatic colorectal cancer. Objectives: (i) To evaluate the depletion in the plasma MET concentration, and (ii) to assess the feasibility of this combination. Methods: Eleven patients were enrolled in this study. They received a median number of 3 two-week cycles of a MET-free diet (3 consecutive days) and FOLFOX6 regimen. Results: The plasma MET concentration was reduced by dietary MET restriction, with a depletion of 58% on the 1st day of MET-free diet. Indeed, we demonstrated the feasibility and good tolerance (nutritional status and toxicity) of the association of a MET-free diet with the FOLFOX regimen. Despite good compliance to the diet, this study revealed the difficulty of administering this combination during further months. Among the 4 patients evaluable for response, 3 experienced a partial response and 1 patient a disease stabilization.
A Single-Institute Experience with Sorafenib in Untreated and Previously Treated Patients with Advanced Hepatocellular Carcinoma
Authors: Balsom Stephanie M. , Li Xiaobai , Trolli Elizabeth , Rose Jeffrey , Bloomston Mark , Patel Tushar , Bekaii-Saab Tanios S.
Published: April 2010

Objectives: Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Sorafenib is considered the standard of care for patients with advanced HCC. Methods: We conducted a retrospective analysis of our cancer center’s experience with sorafenib in patients with advanced HCC. Eligible patients were required to have measurable disease and were allowed to have been refractory (with documented progression) to prior systemic therapies before starting on sorafenib. Results: Twenty-six patients (median age = 56 years) who were treated at the Ohio State University with sorafenib were included in this study. Thirty-eight percent had exposure to prior systemic therapy. The median time to tumor progression was 5.4 months and the median overall survival 7 months. For the patients with exposure to prior systemic therapy, the median time to tumor progression was 9.1 months and is the median overall survival 9.83 months. There were no unexpected toxicities. Conclusion: Sorafenib has interesting activity and acceptable tolerability in patients with advanced HCC, including those who failed prior therapies.
Hemeoxygenase-1 and Renal Ischaemia-Reperfusion Injury
Authors: Ferenbach David A. , Kluth David C. , Hughes Jeremy
Published: April 2010

Degradation by the inducible enzyme hemeoxygenase-1 (HO-1) is the principal route of mammalian heme metabolism. The resultant generation of free iron, carbon monoxide and biliverdin results in myriad actions including promoting cell survival, circulatory integrity and immunomodulation. This review examines the evidence from both human studies and work performed in experimental models implicating the intrinsic heme-HO-1 pathway as important in determining both the susceptibility and severity of acute kidney injury. Additional work using chemical inducers of HO-1 has demonstrated the efficacy of strategies to upregulate enzyme activity in ameliorating the severity of experimental ischaemia-reperfusion injury whilst genetic ablation of HO-1 or pharmacological inhibition of HO-1 activity results in an augmented injury phenotype. There remain a multitude of candidate pathways to account for the therapeutic efficacy of HO-1 induction. Although this may reflect a truly multifactorial mechanism of action, the identification of the relative contribution of key components such as carbon monoxide generation remains critical to allow the rational design of agents for translational application in human disease.
Local Delivery of Angiotensin II Receptor Blockers into the Kidney Passively Attenuates Inflammatory Reactions during the Early Phases of Streptozotocin-Induced Diabetic Nephropathy through Inhibition of Calpain Activity
Authors: Kamal Fadia , Yanakieva-Georgieva Nadezhda , Piao Honglan , Morioka Tetsuo , Oite Takashi
Published: April 2010

Background/Aims: Inhibition of the renin-angiotensin-aldosterone system plays a pivotal role in the prevention and treatment of diabetic nephropathy. Angiotensin II receptor blockers (ARB) exert a renoprotective effect and attenuate the progression of diabetic nephropathy. However, the underlying cellular and molecular mechanisms in the kidney remain to be elucidated. The present study was undertaken to focus on the effect of local angiotensin II type 1 receptor blockade on the inflammatory reaction during the early stages of diabetic nephropathy. Methods and Results: Local ARB treatment significantly reduced urinary protein excretion and serum blood urea nitrogen levels in streptozotocin-induced diabetic nephropathy. In addition, this treatment attenuated monocyte/macrophage infiltration into the glomeruli and the enhanced glomerular expression of endothelial nitric oxide synthase at both the mRNA and protein levels. Immunohistochemical study revealed activation of nuclear factor (NF)-ĸB, as shown by an increase in the expression of the p65 subunit of NF-ĸB and its translocation from the cytoplasm to the nucleus in both tubular epithelial and glomerular cells of the diabetic kidney. Local ARB treatment induced an apparent reduction in p65 nuclear localization and intensity of staining. To search for a common and fundamental candidate that influences endothelial cell function and vascular inflammation, we examined glomerular calpain activity in diabetic rats with or without ARB treatment. Glomerular expression of 145/150-kDa spectrin breakdown products, a specific product of calpain activation, was dramatically increased in diabetic animals while the protein expression reverted to a normal level after ARB treatment. Conclusion: Our findings provide a conceptual basis for the development of therapeutic strategies aiming at local inhibition of the renin-angiotensin system to prevent the progression of diabetic nephropathy.
Management of Adult Patients with Perioperative Pulmonary Hypertension: Technical Aspects and Therapeutic Options
Authors: Winterhalter Michael , Antoniou Theofani , Loukanov Tsvetomir
Published: April 2010

Pulmonary hypertension (PH) is an independent risk factor for increased mortality in patients undergoing heart surgery. Existing chronic PH may be exacerbated by acute post-bypass PH, and this can lead to acute right ventricular failure. The prevention and treatment of right ventricular failure in cardiac surgery is based on three principles: optimize right ventricular preload, improve right ventricular contractility, minimize right ventricular afterload. The last of these may involve specific measures such as the inhalation of nitric oxide (NO) or of the stable prostacyclin analogue iloprost. The advantage of these inhalable substances is their pulmonary selectivity, and the subsequent reduction in systemic side effects. In order to avoid disastrous results in high-risk cardiac surgical patients, intra- and post-operative monitoring with pressure lines, a qualified team that pays attention to details, and an aggressive and early treatment in the operating room with inhaled iloprost and/or NO is necessary. The philosophy of ‘wait and see’ should be abandoned in favour of ‘be suspicious and act early’. In a prospective randomized trial, the efficacies of inhaled iloprost and of inhaled NO in the therapy of PH immediately following weaning from cardiopulmonary bypass in cardiac surgical patients were compared. Iloprost proved to be significantly more effective with respect to mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output than inhaled NO.
Peri-Operative Pulmonary Hypertension in Paediatric Patients: Current Strategies in Children with Congenital Heart Disease
Authors: Gorenflo Matthias , Gu Hong , Xu Zhuoming
Published: April 2010

Congenital heart disease (CHD) is responsible for pulmonary hypertension (PH) in children in about 50% of cases. This pre-operative dynamic pulmonary hypertension can be superimposed and aggravated by acute post-operative PH or persist as chronic PH, especially in children who are not operated on early enough. Inhaled iloprost, a stable prostacyclin analogue, is used for the post-operative management of PH in infants and children with CHD. In a prospective open-label proof-of-concept study, the efficacies of inhaled nitric oxide (iNO) and inhaled iloprost were directly compared. Primary endpoints were the occurrence of a major or minor pulmonary hypertensive crisis. No significant difference between the effects of iNO versus iloprost on peri-operative PH was observed. Neither substance on its own prevented pulmonary hypertensive crises in high-risk infants, so a combination of both substances should be tested in future trials. In China, there are more than 4 million untreated CHD patients. More than 50% of them are untreated adults. Acute pulmonary vasoreactivity tests were performed in CHD patients between 9 months and 43 years of age using inhaled iloprost, in order to find out whether a pre-operative response to inhaled iloprost is a good predictor for the post-operative performance of these patients. The results showed that patient selection criteria for surgery should include both a 20% reduction in pulmonary vascular resistance (PVR) index after iloprost inhalation and a resulting PVR index <11 Wood U/m2. CHD children between 14 days and 11 years of age took part in a placebo-controlled pilot study that investigated the role of aerosolized iloprost in the treatment of PH after corrective surgery. They received either low- or high-dose iloprost or placebo. Inhaled iloprost significantly improved haemodynamics in a dose-dependent manner and prevented reactive PH and pulmonary hypertensive crises in most of these mechanically ventilated children after CHD repair.
Animal Models Related to Congenital Heart Disease and Clinical Research in Pulmonary Hypertension
Authors: Loukanov Tsvetomir , Geiger Ralf , Agrawal Rahul
Published: April 2010

There are several animal models for studying human pulmonary hypertension (PH). An increased flow model in pigs was developed at the University Hospital in Heidelberg in order to simulate congenital heart disease. The high pulmonary blood flow is achieved by installation of a Blalock-Taussig anastomosis. In order to further improve this model by adding a pressure component, the left pulmonary artery is ligated. An acute model, which is used at the Innsbruck Medical University, addresses another disease entity. Human meconium is placed deeply into the trachea of the pigs in order to induce an acute respiratory distress syndrome-like response in the lungs. Animals were randomly assigned to four treatment groups. Inhaled iloprost, due to its pulmonary and intrapulmonary selectivity, was the only substance that significantly reduced intrapulmonary shunt volumes. In humans, PH encompasses multiple disease subtypes. Pulmonary arterial hypertension (PAH) accounts for only 6% of PH cases, however, all existing treatments are indicated only for PAH. This means that for 94% of patients with PH, no specific medication is available. Therefore, huge efforts have been made to better understand the pathophysiology of PH and to detect new signalling pathways that may allow new compounds to be developed that will ultimately improve the prognosis of PAH and non-PAH PH patients. Promising new substances include riociguat, a stimulator of the soluble guanylate cyclase (sGC), as well as cinaciguat, a sGC activator, and an elastase inhibitor. Riociguat (BAY 63-2521) is an oral agent that targets the intact/native form of sGC. It enhances the sensitivity of sGC to low levels of bioavailable nitric oxide (NO) and is also capable of stimulating native sGC independently of NO. Thus, unlike phosphodiesterase-5 inhibitors, the effect of riociguat is not limited by low NO levels. In a multicentre open-label phase II study, riociguat exerted strong and significant effects on pulmonary haemodynamics and exercise capacity in patients with PAH and in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Riociguat is currently being evaluated in phase III clinical trials both in PAH and in CTEPH patients. Clinical studies with riociguat in earlier development stages have addressed PH in lung diseases and systolic left ventricular failure. An elastase inhibitor is currently being investigated in phase I clinical trials in patients with PH owing to chronic obstructive pulmonary disease.