bluuebunny/crossref_metadata_2025 huggingface dataset:
Lentiviral short hairpin RNA screen of genes associated with multidrug resistance identifies PRP-4 as a new regulator of chemoresistance in human ovarian cancer
Authors: Duan Zhenfeng , Weinstein Edward J. , Ji Diana , Ames Rachel Y. , Choy Edwin , Mankin Henry , Hornicek Francis J.
Published: August 2008

Published reports implicate a variety of mechanisms that may contribute to drug resistance in ovarian cancer. The chief aim of this study is to understand the relationship between overexpression of drug resistance associated genes and multidrug resistance in ovarian cancer. Using lentiviral short hairpin RNA collections targeting 132 genes identified from transcriptional profiling of drug-resistant cancer cell lines, individual knockdown experiments were done in the presence of sublethal doses of paclitaxel. Specific genes whose knockdown was found to be associated with cellular toxicity included MDR1 (ABCB1), survivin, and pre-mRNA processing factor-4 (PRP-4). These genes, when repressed, can reverse paclitaxel resistance in the multidrug-resistant cell line SKOV-3TR and OVCAR8TR. Both MDR1 and survivin have been reported previously to play a role in multidrug resistance and chemotherapy-induced apoptosis; however, the effect of PRP-4 expression on drug sensitivity is currently unrecognized. PRP-4 belongs to the serine/threonine protein kinase family, plays a role in pre-mRNA splicing and cell mitosis, and interacts with CLK1. Northern analysis shows that PRP-4 is overexpressed in several paclitaxel-resistant cell lines and confirms that PRP-4 expression could be significantly repressed by PRP-4 lentiviral short hairpin RNA. Both clonogenic and MTT assays confirm that transcriptional repression of PRP-4 could reverse paclitaxel resistance 5-10-fold in SKOV-3TR. Finally, overexpression of PRP-4 in drug-sensitive cells could induce a modest level of drug resistance to paclitaxel, doxorubicin, and vincristine. [Mol Cancer Ther 2008;7(8):2377–85]
Human colorectal tumors and metastases express Gb3 and can be targeted by an intestinal pathogen-based delivery tool
Authors: Falguières Thomas , Maak Matthias , von Weyhern Claus , Sarr Marianne , Sastre Xavier , Poupon Marie-France , Robine Sylvie , Johannes Ludger , Janssen Klaus-Peter
Published: August 2008

The targeting of solid tumors requires delivery tools that resist intracellular and extracellular inactivation, and that are taken up specifically by tumor cells. We have shown previously that the recombinant nontoxic B-subunit of Shiga toxin (STxB) can serve as a delivery tool to target digestive tumors in animal models. The aim of this study was to expand these experiments to human colorectal cancer. Tissue samples of normal colon, benign adenomas, colorectal carcinomas, and liver metastases from 111 patients were obtained for the quantification of the expression of the cellular STxB receptor, the glycosphingolipid globotriaosyl ceramide (Gb3 or CD77). We found that compared with normal tissue, the expression of Gb3 was strongly increased in colorectal adenocarcinomas and their metastases, but not in benign adenomas. Short-term primary cultures were prepared from samples of 43 patients, and STxB uptake was studied by immunofluorescence microscopy. Of a given tumor sample, on average, 80% of the cells could visibly bind STxB, and upon incubation at 37°C, STxB was transported to the Golgi apparatus, following the retrograde route. This STxB-specific intracellular targeting allows the molecule to avoid recycling and degradation, and STxB could consequently be detected on tumor cells even 5 days after initial uptake. In conclusion, the targeting properties of STxB could be diverted for the delivery of contrast agents to human colorectal tumors and their metastases, whose early detection and specific targeting remains one of the principal challenges in oncology. [Mol Cancer Ther 2008;7(8):2498–508]
Nosocomial Infections in a Medical-Surgical Intensive Care Unit
Authors: Aly Nasser Yehia A. , Al-Mousa Haifaa H. , Al Asar El Sayed M.
Published: August 2008

Objective: We aimed to describe the pattern of nosocomial infections in an adult medical-surgical intensive care unit (ICU). Subjects and Methods: A 2-year prospective cohort study of nosocomial infection surveillance in a 15-bed adult combined medical and surgical ICU of Farwaniya Hospital, Kuwait, was carried out. Data were collected between January 2004 and December 2005 using the standard surveillance protocols and nosocomial infection site definitions of the National Nosocomial Infections Surveillance System’s ICU surveillance component. Results: Of 1,173 patients hospitalized in the ICU for an aggregate duration of 6,855 days, 89 patients acquired a total of 140 nosocomial infections; 46 (33%) ventilator-associated pneumonia (VAP), 33 (24%) central-line-associated bloodstream infection and 15 (11%) catheter-associated urinary tract infection, 22 (16%) cutaneous infection and 24 (17%) other infections. The overall patient day rate was 20.6/1,000 patient days. The patient infection rate was 10.6/100 patients at risk. The mean VAP rate was 9.1/1,000 ventilator days (95% CI, 5–13.2), the central-line-associated bloodstream infection rate 5.5/1,000 central line days (95% CI, 3.2–7.8) and the catheter-associated urinary tract infection rate 2.3/1,000 catheter days (95% CI, 1.2–3.4). Of all nosocomial infections, 119 (85%) were culture-confirmed and 21 (15%) were clinically defined culture-negative infections. Of the culture-confirmed nosocomial infections, 81 (68%) were Gram-negative, 32 (27%) Gram-positive and 6 (5%) fungal. The most frequent organism was Pseudomonas aeruginosa (20, 17%), followed by Acinetobacter baumannii (15, 13%), Klebsiella spp. (13, 11%) and Escherichia coli (10, 8%). The crude mortality was 27% among ICU-infected patients. Conclusion: VAP was the most common nosocomial infection in our ICU. Gram-negative organisms were more commonly reported as etiologic agents of ICU infections.
Oral Findings in Newborn Children in and around Mangalore, Karnataka State, India
Authors: George Dilip , Bhat Sham S. , Hegde Sundeep K.
Published: August 2008

Objectives: The aims of this study were to determine the prevalence of normal findings and oral anomalies in newborn children in and around Mangalore, India, within the first week of birth. Subjects and Methods: A gloved index finger, a head torch and an extra-orally placed ruler were used to perform visual examinations in 1,038 newborn babies, who were selected by convenience sampling. The babies were examined by one of the investigators (D.G.). Normal findings like the location of upper labial midline frenum, symmetry of alveolar ridges, anteroposterior/buccolingual and vertical relationship of the alveolar ridges, and oral anomalies like white inclusion cysts that are gingival cyst of infants, Epstein’s pearls and Bohn’s nodules were recorded in a standard format. The findings were statistically analysed. Results: Open bite was present in 102 (9.8%) children. In the anteroposterior relationship, 1,035 (99.7%) had the mandible distal to maxilla. In the buccolingual relationship, the mandible was lingual to the maxilla in 1,035 neonates (99.7%). Gingival cyst of infants was present in 143 (13.8%) of the neonates, Epstein’s pearls in 365 (35.2%) and Bohn’s nodules in 492 (47.4%). Conclusion: The present study exhibits the prevalence of normal findings and anomalies in the neonates. Longitudinal studies are required to assess any significance of the anteroposterior, buccolingual and vertical relationships of the gum pads in the neonates to the future development of occlusion.
Ten-Year Review of Hospital Admissions among Children with Sickle Cell Disease in Kuwait
Authors: Akar Najwa Ali , Adekile Adekunle
Published: August 2008

Objective: This study was designed to document the common causes and patterns of hospitalization among sickle cell disease (SCD) patients in Kuwait. Subjects and Methods: The case files of all SCD patients admitted to the hospital between 1995 and 2004 were studied. Their personal data, hemoglobin genotype, diagnosis on admission, complete blood count, treatment received, length of stay and outcome were documented. Results: Fifty SCD patients aged from 10 months to 14.8 years (mean: 8.7 ± 2.8 years) had 351 admissions over the 10-year period accounting for 0.6% of all admissions to the pediatric wards. The 50 patients were made up of 18 Hb SS, 28 Sβ⁰thal and 4 Hb SD patients. Common causes of admission were vaso-occlusive crisis: 222 (63.2%), acute splenic sequestration crisis: 32 (9.1%), hemolytic crisis: 31 (8.8%) and acute chest syndrome: 23 (6.6%). Stroke was seen in only 1 patient, and bacteriologically proven (Salmonella) acute osteomyelitis in 1 patient. There were no deaths during the study period. Conclusions: Vaso-occlusive crisis was the commonest cause of hospitalization among our SCD patients. Efforts should be intensified to give advice on preventive measures. The use of hydroxyurea should be encouraged in patients with frequent severe pain crises.
Olanzapine in the Treatment of Behavioral Problems Associated with Autism: An Open-Label Trial in Kuwait
Authors: Fido Abdullahi , Al-Saad Samira
Published: August 2008

Objectives: To study the efficacy and safety of olanzapine for the treatment of children with autism associated with disruptive behavior problems. Subjects and Methods: A prospective open-label trial was conducted on 40 male children (mean age 12.2 ± 2.2 years, range 7–17 years) meeting Diagnostic Statistical Manual IV criteria for autism. After a washout period from previous medications (2–14 days), patients received olanzapine (5–10 mg/day) for a 13-week treatment period. The primary efficacy measures were Aberrant Behavior Checklist (ABC) and Clinical Global Impressions-Severity (CGI-S) done at baseline and end of treatment. At the beginning and end of treatment, patients underwent laboratory and physical investigations: ECG, chest X-ray, urinalysis, serum chemistry, blood glucose and lipid profile, hematology and hepatitis B serology. Results: Paired comparison of baseline and 13-week endpoint scores showed significant reductions in ABC subscale scores for irritability (p < 0.0001), lethargy (p < 0.0001), stereotyped behavior (p < 0.005), hyperactivity (p < 0.0001) and inappropriate speech (p < 0.005). Of 40 patients, 12 (30%) were considered as ‘improved’ on CGI-S scores compared to baseline, a statistically significant difference (p < 0.05). No liver enzyme elevation or any other serum biochemical changes resulted from treatment, which was not associated with significant body weight changes or any other treatment-emergent side effects. Conclusions: The study shows that olanzapine treatment can be beneficial in alleviating some behavioral symptoms (irritability, hyperactivity/noncompliance and lethargy/withdrawal) associated with autism. The short period of this trial limits inferences about adverse effects such as body weight increase and tardive dyskinesia. Further long-term placebo-controlled studies of olanzapine are required.
Corticosteroids Can Help Distinguish between Guillain-Barré Syndrome and First Attack of Chronic Inflammatory Demyelinating Neuropathy
Authors: Alexander K. John , Alshubaili Asmahan F. , Santhamoorthy P. , Sharafuddin K.M.
Published: August 2008

Objective: To report a case of acquired demyelinating neuropathy that failed to improve upon treatment with intravenous immunoglobulins and plasmapheresis but responded dramatically to corticosteroids, illustrating the occasional difficulty in distinguishing Guillain-Barré syndrome (GBS) from a first attack of chronic inflammatory demyelinating polyneuropathy (CIDP). Clinical Presentation and Intervention: A 25-year-old previously healthy man was admitted with a 5-day history of ascending areflexic paralysis of all 4 limbs and diagnosed with GBS. On admission, he was administered intravenous immunoglobulins at a dosage of 400 mg/kg/day for 5 days yet continued to worsen. He became quadriparetic by the second week. As there had been no improvement, he was plasmapheresed with 7 sessions of plasma exchange, 50 ml/kg of plasma at each session, including appropriate replacement fluid. After failing to improve within 8 weeks, he was started on intravenous methylprednisolone and a dramatic improvement was observed by the 5th day. He continued to get better on oral prednisolone, was ambulatory with support 4 weeks later and could walk without support on follow-up. Conclusion: This case illustrates that there is a subset of patients initially diagnosed with GBS who do not respond to immunoglobulins or plasmapheresis but do specifically well on steroids. Hence treatment with prednisolone should not be delayed in selective cases of GBS as it may actually be a first episode of CIDP.
Misdiagnosis due to the Hook Effect in Prolactin Assay
Authors: Yener Serkan , Comlekci Abdurrahman , Arda Nuri , Men Suleyman , Yesil Sena
Published: August 2008

Objectives: To describe a patient who was misdiagnosed as having a nonfunctional pituitary tumor due to the hook effect on prolactin measurements. Clinical Presentation and Intervention: A 45-year-old female was admitted with visual disturbances, panhypopituitarism and central diabetes insipidus due to pituitary tumor recurrence. She had been operated 4 times earlier and received cranial irradiation for a suspected nonfunctional pituitary adenoma. Serum prolactin was moderately elevated (164.5 ng/ml), but increased markedly after 1:100 dilution to 14,640 ng/ml. Diagnosis of a giant macroprolactinoma was made and cabergoline was started. Prolactin level normalized and a mild shrinkage of the tumor was achieved after 12 months of therapy. Conclusion: The hook effect must be kept in mind while evaluating a giant pituitary adenoma with moderately elevated prolactin levels. This way unnecessary surgical procedures or irradiation may be avoided.
Emergence of High-Level Vancomycin-Resistant Staphylococcus aureus in the Imam Khomeini Hospital in Tehran
Authors: Aligholi Marzieh , Emaneini Mohammad , Jabalameli Fereshteh , Shahsavan Shadi , Dabiri Hosein , Sedaght Hossein
Published: August 2008

Objective: The objective of the study was to investigate the prevalence of vancomycin-resistant Staphylococcus aureus (VRSA). Materials and Methods: Three hundred and fifty-six S. aureus isolates from the Imam Khomeini hospital in Tehran, Iran, were evaluated for methicillin and decreased vancomycin susceptibility by the microbroth dilution method. The mecA, vanAand vanB genes were targeted by polymerase chain reaction. Results: Of the 356 isolates, 149 (41.85%) S. aureus strains were resistant to methicillin. Two strains of methicillin-resistant S. aureus were VRSA strains. One isolate, Teaching Hospital-1 (TEH-1), had a vancomycin minimum inhibitory concentration (MIC) of 64 µg/ml and was susceptible to teicoplanin while the other isolate (TEH-2) had a vancomycin and teicoplanin MIC of 512 and >256 µg/ml, respectively, and was positive for the vanA gene. Conclusion: This report shows that the emergence of VRSA in Iran warrants active microbiological surveillance and careful monitoring of vancomycin therapy.
Inflammatory Markers in the Tears of Patients with Ocular Surface Disease
Authors: Acera Arantxa , Rocha Germán , Vecino Elena , Lema Isabel , Durán Juan A.
Published: August 2008

Purpose: To determine the concentration of interleukins (IL-1β and -6) and matrix metalloproteinase 9 (pro-MMP-9) in the tears of patients with different ocular surface diseases and to examine the possible relationship between the disorders and molecular inflammation. Methods: 77 patients diagnosed as having different ocular surface disorders and 18 normal control subjects were studied. Patients were routinely examined and separated into 5 groups: (1) control, (2) blepharitis, (3) ocular allergic disease, (4) dry eye and (5) conjunctivochalasis. Ten microliters of tears were collected by a Weck cell sponge. The concentrations of IL-1β, IL-6 and pro-MMP-9 were measured by enzyme-linked immunosorbent assay, and the MMP-9 activity was evaluated with gelatin zymography. Results: Levels of IL-1β and IL-6 in tear fluid were significantly higher in conjunctivochalasis (p = 0.0062 and p = 0.0134) than in the control group. Pro-MMP-9 levels were significantly elevated in blepharitis (p = 0.013), in allergic eye disease, in dry eye and in conjunctivochalasis (all p < 0.001), in comparison to controls. Conclusions: Pro-MMP-9 levels in tears are elevated in all of the studied pathologies especially in ocular allergy and conjunctivochalasis. However, IL-1β and IL-6 were only found to be overexpressed in conjunctivochalasis. These findings illustrate the selective implication of different molecules in each disorder.
IGFBP-1 Levels in Cervicovaginal Secretions before and after Amniocentesis
Authors: Devlieger R. , Verhaeghe J. , Coopmans W. , Deprest J.A.
Published: August 2008

Background: To evaluate the levels of insulin-like growth factor-binding protein-1 (IGFBP-1) in cervicovaginal secretions before and after midtrimester amniocentesis and relate to clinical outcome. Methods: 100 consecutive amniocentesis procedures were studied. We measured the IGFBP-1 concentration by radioimmunoassay in a cervicovaginal specimen before and after mid-trimester amniocentesis. The post-amniocentesis occurrence of vaginal loss of fluid or blood and abdominal pain was assessed by questionnaire. Results: In 6 cases there was a 100-fold increase in IGFBP-1 levels after amniocentesis. Loss of fluid per vaginam occurred in 4 (67%) of these pregnancies, compared to 3.2% of pregnancies without significant surge (p < 0.0001). In addition, post-procedural abdominal pain was more common among women with increased IGFBP-1 levels after amniocentesis (50 vs. 14%, p = 0.05). Two (33%) of the 6 patients with increased IGFBP-1 after amniocentesis delivered prior to 37 weeks as a result of spontaneous preterm labor and/or preterm ruptured membranes, compared to 7 (7%) in the group without surge in IGFBP-1 (p = 0.09). Conclusion: Increased post-procedure IGFBP-1 levels are after mid-trimester amniocenteses are related to procedure-related complications like abdominal pain and subsequent amniotic fluid leakage.
Pentoxifylline Inhibits Transforming Growth Factor-Beta Signaling and Renal Fibrosis in Experimental Crescentic Glomerulonephritis in Rats
Authors: Ng Yee-Yung , Chen Yung-Ming , Tsai Tun-Jun , Lan Xiao-Ru , Yang Wu-Chang , Lan Hui Y.
Published: August 2008

Background/Aims: Pentoxifylline (PTX) has been shown to inhibit renal inflammation in a rat model of crescentic glomerulonephritis. The present study investigated the role of PTX in renal fibrosis in rats with crescentic glomerulonephritis. Methods: A rat model of accelerated anti-glomerular basement membrane glomerulonephritis was induced and treated with PTX or vehicle control for 3, 7, 14 and 28 days. The therapeutic effect and mechanism of PTX on renal fibrosis were examined by Northern blot and immunohistochemistry. Results: Diseased rats treated with vehicle control developed a severe crescentic glomerulonephritis with progressive renal fibrosis identified by a marked accumulation of α-SMA+ myofibroblasts and collagen matrix. This was associated with tubular epithelial-myofibroblast transition as evident by de novo expression of α-SMA and a loss of E-cadherin on damaged tubular epithelial cells. Further studies revealed that severe renal fibrosis was associated with upregulation of renal TGF-β1 and activation of TGF-β/Smad signaling, which was blocked by treatment with PTX. Conclusions: PTX may be an anti-fibrosis agent capable of inhibiting renal fibrosis in a rat model of crescentic glomerulonephritis. Blockade of TGF-β1 expression and Smad2/3 activation may be a mechanism by which PTX inhibits renal fibrosis.
A Phase II Trial of the Novel Serotonin Type 3 Receptor Antagonist Ramosetron in Japanese Male and Female Patients with Diarrhea-Predominant Irritable Bowel Syndrome
Authors: Matsueda K. , Harasawa S. , Hongo M. , Hiwatashi N. , Sasaki D.
Published: August 2008

Background: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder. Serotonin type 3 (5-HT3) receptor antagonist alosetron hydrochloride is indicated for women with chronic, severe diarrhea-predominant IBS who have not responded adequately to conventional therapy. However, whether or not the therapeutic efficacy of 5-HT3 receptor antagonists has gender difference is uncertain. Methods: A double-blind, placebo-controlled, parallel-group, comparative study was conducted to evaluate the effect of novel 5-HT3 receptor antagonist, ramosetron hydrochloride, in male and female patients with diarrhea-predominant IBS. 418 subjects were randomized (109 subjects: placebo, 105 subjects: 1 µg, 103 subjects: 5 µg, and 101 subjects: 10 µg) and administered the study drug once daily. Results: The monthly responder rates of ‘Patient-reported global assessment of relief of irritable bowel syndrome symptoms’ in the 5- and 10-µg ramosetron hydrochloride-administered groups were higher than the placebo group (26.92, 42.57, and 43.01% for placebo, 5 and 10 µg). Moreover, the difference of the responder rate in comparison with the placebo group was similar in males and females. As for safety, there was tolerability at doses up to 10 µg. Conclusion: Ramosetron is an effective and well-tolerated treatment not only for female IBS patients but also for male patients.
Endoscope Images of Schönlein-Henoch Purpura
Authors: Nishiyama Ryu , Nakajima Noriko , Ogihara Akifumi , Oota Souichirou , Kobayashi Shun , Yokoyama Kiyoshi , Oonishi Masahiko , Miyamoto Shunpachi , Akai Yuuichi , Watanabe Toshikazu , Uno Akitake , Mizuno Shigeaki , Ootani Takeshi , Tanaka Naohide , Moriyama Mituhiko
Published: August 2008

Background/Aims: Schönlein-Henoch purpura (SHP) is a systemic condition characterized by purpura associated with leukocytoclastic vasculitis. SHP diagnosis is more difficult in infrequent cases where gastrointestinal (GI) symptoms precede purpura. This report examines 11 cases of SHP at our hospital with specific regard to the incidences and details of GI symptoms. Methods: The clinical manifestations and endoscopic findings were investigated for their utility in SHP diagnosis. Results: Among the 11 cases, 3 showed GI symptoms prior to other manifestations. In terms of GI symptoms, abdominal pain was reported in all 11 cases, diarrhea in 4 cases, and bloody stools in 3 cases. Endoscopic findings were seen in the stomach in 7/10 cases, in the small intestine including the duodenum in 10/11 cases, and in the large intestine in 6/10 cases. The frequency of ulcer formation was significantly higher in the small intestine (including the duodenum) than in the stomach. Multiple specific erythematosus lesions were observed in the stomach and large intestine. Conclusion: Familiarity with characteristic endoscopic findings and careful observation of all GI findings are essential for diagnosing SHP in cases in which GI tract symptoms precede cutaneous findings.
Interaction between CD147 and P-Glycoprotein and Their Regulation by Ubiquitination in Breast Cancer Cells
Authors: Wang Wen-Juan , Li Qing-Quan , Xu Jing-Da , Cao Xi-Xi , Li Hai-Xia , Tang Feng , Chen Qi , Yang Jin-Ming , Xu Zu-De , Liu Xiu-Ping
Published: August 2008

Background: Multidrug-resistant cancer cells overexpressing P-glycoprotein (P-gp) display variations in invasive and metastatic ability through the upregulation of the extracellular matrix metalloproteinase (MMP) inducer (CD147). However, the direct linkage between these two proteins is still unclear. Methods: We used immunoprecipitation, immunofluorescence analysis, migration and invasion assays, drug sensitivity assay and Western blot to measure the physical and functional interaction between P-gp and CD147. Then we transfected vectors carrying ubiquitin C-terminal hydrolase L1 (UCH-L1) or UCH-L1 siRNA into MCF7 and MCF7/Adr cells, respectively, and investigated the role of UCH-L1 in the regulation of the expression and degradation of P-gp, CD147 and MMP-1, MMP-2, and MMP-9 by quantitative real-time polymerase chain reaction, Western blot and immunoprecipitation. Results: In this paper, we showed that P-gp and CD147 interacted with each other, and that the ubiquitin-proteasome pathway played an important role in the turnover of them. In addition, we found that inhibition of N-glycosylation increased the ubiquitination and degradation of P-gp and CD147, and affected their function. UCH-L1 not only regulated the expression of P-gp, CD147 and MMP-1, MMP-2, and MMP-9, but also the ubiquitination and degradation of P-gp and CD147 in breast cancer cells. Conclusion: Our results demonstrate a mechanism underlying the linkage between multidrug resistance and tumor metastasis, and suggest for the first time that modulating the ubiquitination of P-gp and CD147 might be a novel method for tumor therapy.
The Beck Depression Inventory Requires Modification in Scoring before Use in a Haemodialysis Population in the UK
Authors: Grant Donna , Almond Michael K. , Newnham Alison , Roberts Pauline , Hutchings Andrew
Published: August 2008

Background: There are high rates of mental illness, especially depression in people with end-stage renal disease (ESRD) on haemodialysis (HD). Depression can be difficult to diagnose, as depression and the medical problem share many symptoms. It is essential that the diagnosis of a depressive illness be accurately made in order that subsequent psychiatric management can occur. This is the first study done in the UK which aims to validate a simple method for detecting depression, the Beck Depression Inventory (BDI), in people on HD against a structured psychiatric interview with a trained psychiatrist using the ICD-10 classification of depression. The BDI is validated in a normal population, but in patients with physical ill health there has been a difficulty in defining appropriate cut-off scores. Methods: Patients dialysing for over 3 months from a single HD unit were eligible for participation. Patients were excluded if a known psychiatric illness existed or if they were receiving medication for a psychiatric illness. Patients who had a recent major illness requiring hospitalisation were excluded. 57 consenting participants completed the self-reported BDI. Within the next week a psychiatrist carried out a clinical interview to diagnose depression, based on the ICD-10 classification of a depressive disorder. Patients were classified as not being depressed or having mild, moderate or severe depression according to their BDI score or the ICD-10 classification. Results: The BDI gave more scores for depression and more severe scores than ICD-10. 30 cases had scores which agreed, 27 cases resulted in a higher BDI score than the ICD-10 classification, in no case was the ICD-10 classification more severe (Wilcoxon signed rank test p < 0.001). All 7 diagnosed as being depressed by clinical interview were also depressed by BDI, although in 2 cases the BDI worsened the depression score. Conclusions: Using the general population cut-off score, the BDI significantly overdiagnosed depression in this HD population. This study defines a BDI cut-off score which more reliably detects major depression in a HD population. Unrecognised depression remains high in those with no known psychiatric illness within the HD populations.
Exploring Evolution in Ceboidea (Platyrrhini, Primates) by Williams-Beuren Probe (HSA 7q11.23) Chromosome Mapping
Authors: Picone Barbara , Dumas Francesca , Stanyon Roscoe , Lannino Antonella , Bigoni Francesca , Privitera Orsola , Sineo Luca
Published: August 2008

The ancestral platyrrhine karyotype was characterised by a syntenic association of human 5 and a small segment of human 7 orthologues. This large syntenic association has undergone numerous rearrangements in various phylogenetic lines. We used a locus-specific molecular cytogenetic approach to study the chromosomal evolution of the human 7q11.23 orthologous sequences (William-Beuren syndrome, WS) in various Ceboidea (Platyrrhini) species. The fluorescent in situ hybridisation of the WS probe revealed a two-way pattern of chromosomal organisation that suggests various evolutionary scenarios. The first pattern (seen in Callimico and Saimiri ) includes a fairly simple disruption of the 7/5 syntenic association by a chromosome fission. The second pattern (seen in Atelinae, Alouattinae and in Callicebus ) is characterised by an increasing complexity in the 7/5 association as a consequence of a series of inversions and translocations resulting in different syntenic associations. These data support recent proposals for phylogenomic groupings of New World monkeys. The study also illustrates how single-locus probe hybridisations can reveal intrachromosomal rearrangements.
Effect of Dietary Calcium and Dairy Proteins on the Adipose Tissue Gene Expression Profile in Diet-Induced Obesity
Authors: Pilvi Taru K. , Storvik Markus , Louhelainen Marjut , Merasto Saara , Korpela Riitta , Mervaala Eero M.
Published: August 2008

Background/Aims: Calcium and dairy proteins have been postulated to explain why the intake of dairy products correlates inversely with body mass index in several populations. We have shown that a high-calcium diet with whey protein attenuates weight gain and now we describe the effects of this diet on adipose tissue gene expression. Methods: Nine-week-old C57Bl/6J mice were divided into two groups (n = 10/group). The control diet was a standard high-fat diet (60% of energy) low in calcium (0.4%). The whey protein diet was a high-calcium (1.8%), high-fat diet with whey protein. After the 21-week treatment, adipose tissue transcript profiling (2 mice/group) was performed using Affymetrix Mouse Genome 430 2.0. Results: The high-calcium diet with whey protein altered the expression of 129 genes (± 1.2 fold). Quantitative RT-PCR analysis confirmed the significant up-regulation of Adrb3 (p = 0.002) and leptin (p = 0.0019) in the high-calcium whey group. Insulin and adipocytokine signaling pathways were enriched among the up-regulated genes and the fatty acid metabolism pathway among the down-regulated genes. Conclusions: High-calcium diet with whey protein significantly modifies adipose tissue gene expression. These preliminary findings reveal that targets of a high-calcium diet with whey protein include genes for Adrb3 and leptin, and help to explain how the intake of dairy products might attenuate obesity.
The Global Burden of Chronic Kidney Disease: How Valid Are the Estimates?
Authors: Glassock Richard J. , Winearls Christopher
Published: August 2008

Background/Aims: The values for the global prevalence of chronic kidney disease (CKD) are poorly understood. Current classification schemas may overstate the prevalance of CKD. This minireview analyzes the pitfalls in the use of current classification approaches for identifying CKD on a global basis. Methods: Literature review and comment. Results: Published estimates for the global burden of CKD are likely to be incorrect and inflated. Overestimations of prevalence have occurred due to flaws in the classification systems employed and in ascertainment methods. Conclusions: A revision of the current system of diagnosing and classifying CKD is needed in order to determine with greater precision true global burden of CKD. A new system is proposed.
Extremes of Glycemic Control (HbA1c) Increase Hospitalization Risk in Diabetic Hemodialysis Patients in the USA
Authors: Williams M.E. , Lacson, Jr. E. , Teng M. , Hakim R.M. , Lazarus J.M.
Published: August 2008

Background/Aims: Because the relation between glycemic control and clinical outcomes found in the general diabetic population has not been established in diabetic hemodialysis patients, we evaluated the association between glycemic control and hospitalization risk. Methods: We performed a primary retrospective data analysis on 23,829 hemodialysis patients with diabetes mellitus. Hemoglobin A1c at baseline and hospitalization events over the subsequent 12 months were analyzed and logistic regression models constructed for unadjusted, case mix-adjusted and case mix plus lab- adjusted data. Models were also constructed for cardiovascular, vascular access and sepsis hospitalizations. Results: Eighty percent had type 2 DM, 5% type 1 and 14% not specified. The groups had similar mean HbA1c levels, 6.8 ± 1.6%. Among all patients, the mean HbA1c values were >7% in 35%. The odds ratio of hospitalizations grouped by baseline HbA1c was significant at extremes of <5% and >11%. Similar relationships were evident for the subset of type 2 DM and in the analysis for hospitalizations due to sepsis. Conclusion: Extremely high and low HbA1c values are associated with hospitalization risk in diabetic hemodialysis patients. Prospective studies are needed to determine whether meeting recommended HbA1c targets might improve outcomes without posing additional risks in this population.
Oxidized Low-Density Lipoprotein and Oxidative Stress in the Development of Glomerulosclerosis
Authors: Lee Hyun Soon , Song Chi Young
Published: August 2008

Glomerulosclerosis frequently complicates most renal diseases and is characterized by mesangial matrix accumulation. Oxidized low-density lipoprotein (Ox-LDL) could induce oxidative stress and profibrotic gene expression in mesangial cells. This article will review our current understanding of the pathogenetic mechanisms of lipid-mediated glomerulosclerosis, emphasizing the fibrogenic signaling cascades triggered by Ox-LDL. In addition, therapeutic strategies to prevent the development of Ox-LDL-mediated glomerulosclerosis will be discussed.
Influence of Platelet-Rich Plasma on Chondrogenic Differentiation and Proliferation of Chondrocytes and Mesenchymal Stem Cells
Authors: Drengk Anja , Zapf Antonia , Stürmer Ewa Klara , Stürmer Klaus Michael , Frosch Karl-Heinz
Published: August 2008

Background/Aims: Autologous chondrocyte (CC) transplantation has the disadvantages of requiring two surgical interventions and in vitro expansion of cells, implying the risk of cellular dedifferentiation. Our clinical aim is to develop a one-step procedure for autologous CC transplantation, i.e. harvesting, isolation and reimplantation of CC performed in one single surgical procedure. Platelet-rich plasma (PRP) is a source of autologous growth factors reported to have mitogenic effects. The objective of this study was to test the influence of PRP as an autologous scaffold on freshly isolated CC and mesenchymal stem cells (MSC). Methods: CC and MSC were subjected to two- or three-dimensional (3D) growth systems, either with or without PRP. Chondrogenic differentiation was determined via quantification of collagen type II mRNA and immunohistochemical staining. Results: We observed a proliferative effect for MSCs exposed to PRP in monolayer culture and an increase in the expression of chondrogenic markers when cells are exposed to a 3D environment. CCs exposed to PRP show a decrease in the chondrogenic phenotype with increasing proliferative activity. Conclusion: PRP has a proliferative effect on CCs and MSCs. In a one-step procedure for autologous CC transplantation, this might be an advantage over other scaffold materials, but confirmation in in vivo studies is required.
Enrichment of Human β1bri/α6bri/CD71dim Keratinocytes after Culture in Defined Media
Authors: Lorenz Katrin , Rupf Thomas , Salvetter Jürgen , Bader Augustinus
Published: August 2008

Stem cell-like keratinocytes are responsible for the high regenerative potential of the skin. For clinical applications using keratinocytes in artificial skin constructs, it is suitable to work with serum-free medium under defined conditions. This is also true for the preceding expansion of the stem cell-like keratinocyte population. Therefore, we analyzed the effect of a serum-free medium on the population distribution in comparison to an established serum-containing standard medium for keratinocyte culture. We quantified the freshly isolated as well as cultured primary human keratinocytes by their expression of the β1 integrin (CD29) in combination with the expression of the α6 integrin (CD49f) and the transferrin receptor (CD71) by flow cytometric methods. We were able to show that cultivation with serum-free medium induces a switch of the cell population to higher expression of the β1 integrin. In addition, the proportion of the α6bri/ CD71dim-expressing keratinocyte cell population was enhanced about 35.4 ± 6.56% after cultivation with serum-free medium. Culture in serum-containing medium increased this proportion of the keratinocyte cell population only about 17.3 ± 8.06%, when compared to the α6bri/ CD71dim-expressing keratinocyte cell population measured directly after isolation. Our data show that the applied culture conditions already have an enormous impact on the development of a stem cell-like phenotype of keratinocytes. This work demonstrates that the serum-free medium significantly increases the proportion of β1bri/α6bri/CD71dim-expressing keratinocytes. In conclusion, these findings implicate new applications in keratinocyte stem cell research and regenerative medicine.
Low Serum Uric Acid Level Is a Risk Factor for Death in Incident Hemodialysis Patients
Authors: Lee S.M. Kurt , Lee Andrew L. , Winters Thomas J. , Tam Emily , Jaleel Mohammed , Stenvinkel Peter , Johnson Richard J.
Published: August 2008

Background: A reverse epidemiology of classic cardiovascular risk factors was observed in hemodialysis patients with a high comorbidity burden. We hypothesized that uric acid, a novel cardiovascular risk factor, also has an altered association with survival in these patients. Methods: A retrospective study was conducted on 168 consecutive outpatient hemodialysis patients over a 6-year period. Serum uric acid, albumin levels and relevant laboratory information were recorded monthly. The disease severity was assessed using Comorbidity Index (CoI) scores. Patients were stratified into 3 groups according to their serum uric acid concentrations: group I was the lowest quintile, group II was the middle 3 quintiles and group III was the highest quintile. The risks of death were calculated utilizing a Cox regression model. Results: Using group II as a reference group, the hazard ratio of group I was 2.23 [95% confidence interval (CI) 1.21–4.11, p = 0.01] and group III was 0.89 (95% CI 0.47–1.71, p = 0.74). The serum uric acid levels correlated inversely with CoI scores (r = –0.31, 95% CI –0.44 to –0.17, p < 0.0001) and positively with serum albumin levels (r = 0.35, 95% CI 0.21–0.48, p < 0.0001). Conclusion: Low serum uric acid is a mortality risk factor in incident hemodialysis patients with a high comorbidity burden and hypoalbuminemia.
Effects of Angiotensin II Type 1 Receptor Blocker on Albumin-Induced Cell Damage in Human Renal Proximal Tubular Epithelial Cells
Authors: Takao Toshihiro , Horino Taro , Kagawa Toru , Matsumoto Reiko , Inoue Kousuke , Taguchi Takafumi , Morita Tatsuhito , Iwasaki Yasumasa , Hashimoto Kozo , Terada Yoshio
Published: August 2008

Background/Aims: Proteinuria is not merely a marker of chronic nephropathies, but may also be involved in the progression to end-stage renal failure. We investigated the effect of angiotensin II type 1 receptor blockers (ARBs) on albumin-induced cell damage in human renal proximal tubular epithelial cells (RPTEC). Methods: The N-acetyl-β- D-glucosaminidase (NAG) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels in the medium after albumin treatment with ARBs were determined by commercially available kits. The levels of p22phox protein in RPTEC were measured using Western blotting after albumin treatment with ARBs. Angiotensin II concentrations in cell media and cell lysates were assayed with a commercially available kit. Results: Human albumin (0.1–10 mg/ml) dose-dependently increased NAG release and olmesartan or valsartan (10–9–10–7 mol/l) showed a significant reduction on albumin (1 mg/ml)-induced NAG release in RPTEC. Albumin treatment (1 mg/ml) showed significant increases in p22phox protein levels in RPTEC and ARBs significantly decreased albumin-induced p22phox protein levels. Significant increases in 8-OHdG levels were observed in the albumin (1 mg/ml)-treated group and ARBs markedly reduced albumin-induced 8-OHdG levels in RPTEC. Human albumin dose-dependently increased angiotensin II concentrations in both cell media and lysates. Conclusion: These observations suggest renal tubular cell-protective properties of ARBs related to decreased oxidative stress during proteinuria.
Endothelial Cell PECAM-1 Promotes Atherosclerotic Lesions in Areas of Disturbed Flow in ApoE-Deficient Mice
Authors: Harry Brian L. , Sanders John M. , Feaver Ryan E. , Lansey Melissa , Deem Tracy L. , Zarbock Alexander , Bruce Anthony C. , Pryor Andrew W. , Gelfand Bradley D. , Blackman Brett R. , Schwartz Martin A. , Ley Klaus
Published: August 2008

Objective—

Platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) has recently been shown to form an essential element of a mechanosensory complex that mediates endothelial responses to fluid shear stress. The aim of this study was to determine the in vivo role of PECAM-1 in atherosclerosis.

Methods and Results—

We crossed C57BL/6
Pecam1
−/−
mice with apolipoprotein E-deficient (
Apoe
−/−
) mice. On a Western diet,
Pecam1
−/−
Apoe
−/−
mice showed reduced atherosclerotic lesion size compared to
Apoe
−/−
mice. Striking differences were observed in the lesser curvature of the aortic arch, an area of disturbed flow, but not in the descending thoracic or abdominal aorta. Vascular cell adhesion molecule-1 (VCAM-1) expression, macrophage infiltration, and endothelial nuclear NF-κB were all reduced in
Pecam1
−/−
Apoe
−/−
mice. Bone marrow transplantation suggested that endothelial PECAM-1 is the main determinant of atherosclerosis in the aortic arch, but that hematopoietic PECAM-1 promotes lesions in the abdominal aorta. In vitro data show that siRNA-based knockdown of PECAM-1 attenuates endothelial NF-κB activity and VCAM-1 expression under conditions of atheroprone flow.

Conclusion—

These results indicate that endothelial PECAM-1 contributes to atherosclerotic lesion formation in regions of disturbed flow by regulating NF-κB-mediated gene expression.
Apolipoprotein A-I Tryptophan Substitution Leads to Resistance to Myeloperoxidase-Mediated Loss of Function
Authors: Peng Dao-Quan , Brubaker Gregory , Wu Zhiping , Zheng Lemin , Willard Belinda , Kinter Michael , Hazen Stanley L. , Smith Jonathan D.
Published: August 2008

Objective—

Apolipoprotein A-I (apoAI) acts as an ABCA1-dependent acceptor of cellular phospholipids and cholesterol during the biogenesis of HDL, but this activity is susceptible to oxidative inactivation by myeloperoxidase. We tried to determine which residues mediated this inactivation and create an oxidant-resistant apoAI variant.

Methods and Results—

Mass spectrometry detected the presence of tryptophan, methionine, tyrosine, and lysine oxidation in apoAI recovered from human atheroma. We investigated the role of these residues in the myeloperoxidase-mediated loss of apoAI activity. Site-directed mutagenesis and chemical modification were used to create variants of apoAI which were tested for ABCA1-dependent cholesterol acceptor activity and oxidative inactivation. We previously reported that tyrosine modification is not required for myeloperoxidase-induced loss of apoAI function. Lysine methylation did not alter the sensitivity of apoAI to myeloperoxidase, whereas site-specific substitution of apoAI methionine to valine increased the sensitivity of apoAI to myeloperoxidase. ApoAI tryptophan residues were identified as essential in apoAI function and oxidant sensitivity as substitution of all four apoAI tryptophan residues to leucine led to loss of function, but the conservative substitution to phenylalanine retained full function and was resistant to oxidative inactivation.

Conclusions—

Tryptophan modification of apoAI is primarily responsible for the myeloperoxidase-mediated loss of the cholesterol acceptor activity of apoAI.
Tumor Necrosis Factor-α Downregulates Endothelial Nitric Oxide Synthase mRNA Stability via Translation Elongation Factor 1-α 1
Authors: Yan Guijun , You Bei , Chen Shao-Ping , Liao James K. , Sun Jianxin
Published: August 2008

Endothelium-derived nitric oxide (NO) is an important regulator of vascular function. NO is produced by endothelial NO synthase (eNOS), whose expression is downregulated by tumor necrosis factor (TNF)-α at the posttranscriptional level. To elucidate the molecular basis of TNF-α–mediated eNOS mRNA instability, eNOS 3′ untranslated region (3′-UTR) binding proteins were purified by RNA affinity chromatography from cytosolic fractions of TNF-α–stimulated human umbilical vein endothelial cells (HUVECs). The formation of 3′-UTR ribonucleoprotein complexes, with molecular weight of 52 and 57 kDa, was increased by TNF-α. Matrix-assisted laser desorption ionization time-of-flight mass spectrometric analysis of the 52-kDa protein identified 3 peptides that comprise the peptide sequence of translation elongation factor 1-α 1 (eEF1A1). In HUVECs, TNF-α rapidly increased eEF1A1 expression, which is maximal after 1 hour and persists for up to 48 hours. RNA gel mobility-shift and UV cross-linking assays indicated that recombinant glutathione
S
-transferase–eEF1A1 fusion protein specifically binds to a UC-rich sequence in the 3′-UTR of eNOS mRNA. In addition, the domain III of eEF1A1 mediates the binding of eNOS 3′-UTR in eEF1A1. Overexpression of eEF1A1 markedly attenuated the expression of eNOS and luciferase gene fused with eNOS 3′-UTR in both COS-7 cells and bovine aortic endothelial cells (BAECs). Furthermore, adenovirus-mediated overexpression of eEF1A1 increased eNOS mRNA instability, whereas knockdown of eEF1A1 substantially attenuated TNF-α–induced destabilization of eNOS mRNA and downregulation of eNOS expression in HUVECs. These results indicate that eEF1A1 is a novel eNOS 3′-UTR binding protein that plays a critical role in mediating TNF-α–induced decrease in eNOS mRNA stability.
Cardiorespiratory Fitness as a Predictor of Fatal and Nonfatal Stroke in Asymptomatic Women and Men
Authors: Hooker Steven P. , Sui Xuemei , Colabianchi Natalie , Vena John , Laditka James , LaMonte Michael J. , Blair Steven N.
Published: August 2008

Background and Purpose—

Prospective data on the association between cardiorespiratory fitness (CRF) and stroke are largely limited to studies in men or do not separately examine risks for fatal and nonfatal stroke. This study examined the association between CRF and fatal and nonfatal stroke in a large cohort of asymptomatic women and men.

Methods—

A total of 46 405 men and 15 282 women without known myocardial infarction or stroke at baseline completed a maximal treadmill exercise test between 1970 and 2001. CRF was grouped as quartiles of the sex-specific distribution of maximal metabolic equivalents achieved. Mortality follow-up was through December 31, 2003, using the National Death Index. Nonfatal stroke, defined as physician-diagnosed stroke, was ascertained from surveys during 1982 to 2004. Cox regression models quantified the pattern and magnitude of association between CRF and stroke.

Results—

There were 692 strokes during 813 944 man-years of exposure and 171 strokes during 248 902 woman-years of exposure. Significant inverse associations between CRF and age-adjusted fatal, nonfatal, and total stroke rates were observed for women and men (
P
trend
≤0.05 each). After adjusting for several cardiovascular disease risk factors, the inverse association between CRF and each stroke outcome remained significant (
P
trend
<0.05 each) in men. In women, the multivariable-adjusted relationship between CRF and nonfatal and total stroke remained significant (
P
trend
≤0.01 each), but not between CRF and fatal stroke (
P
trend
=0.18). A CRF threshold of 7 to 8 maximal metabolic equivalents was associated with a substantially reduced rate of total stroke in both men and women.

Conclusions—

These findings suggest that CRF is an independent determinant of stroke incidence in initially asymptomatic and cardiovascular disease-free adults, and the strength and pattern of the association is similar for men and women.